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Sodium Butyrate Ameliorates Renal Tubular Lipid Accumulation Through the PP2A-TFEB axis in Diabetic Nephropathy

ABSTRACT: Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266108 | GEO | 2024/10/31

REPOSITORIES: GEO

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Project description:Diabetic nephropathy (DN) as a common complication of diabetes is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short chain fatty acid in the metabolic products of intestinal bacterium, and its kidney protective effect has been reported in DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, eight-week-male db/db mice which were established DN mice were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5g/kg/day) and the DN group (DN mice treated with saline). Also, the normal db/m mice were used as NC group. Further, blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured in three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate profiling of lncRNAs and messenger RNAs (mRNAs). Bioinformatic analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested by quantitative real-time polymerase chain reaction (qRT-PCR) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that 17 lncRNAs and 180 mRNAs reversely changed in DN+NaB group when compared with those in DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed these lncRNAs interacted with 155 key mRNAs. The co-expression networks of mRNAs associated to immune response, antigen processing and presentation and acute inflammatory response to antigenic stimulus. The qRT-PCR data showed that eight mRNAs and seven lncRNAs were dysexpressed by NaB in DN mice and mesangial cell under high glucose condition. Furthermore, the co-expression network of inflammation related lncRNAs and mRNAs demonstrated that those 17 reversed lncRNAs and 37 mRNAs also play essential roles in inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes induced renal dysfunction and regulates transcriptome changes in DN. NaB related lncRNA-mRNA may play roles in the protective effect of NaB in DN.

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Sodium Butyrate Ameliorates Renal Tubular Lipid Accumulation Through the PP2A-TFEB axis in Diabetic Nephropathy

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